This invention relates to novel 1,2-dihydropyrido-[3,4-b]pyrazines, also known as 1-deaza-7,8-dihydropteridines.
The antimitotic chemical agents commonly known as spindle poisons are plant products of which the best known are colchicine, podophyllotoxin, and the vinca alkaloids. [L. Wilson, J. R. Bamburg, S. B. Mizel, L. M. Grisham and K. M. Creswell, Federation Proceedings, 33, 158 (1974)]. Two members of the latter, vincristine and vinblastine, are currently used clinically in the treatment of neoplasms. Although these agents produce a number of biochemical actions such as the inhibition of macromolecular synthesis, their primary effect is to prevent mitosis by interfering with the function of microtubules, which results in the accumulation of cells in metaphase. In addition, several benzimidazol-2-ylcarbamates have been introduced as fungicides, anthelmintics and antitumoral agents. [L. C. Davidse and W. Flach, J. Cell Biol., 72, 174 (1977). These compounds also prevent mitosis and their biological activity can probably be attributed to interference with the formation or functioning of microtubules.
U.S Pat. No. 4,450,160 to Temple et al discloses that certain 1,2-dihydropyrido[3,4-b]pyrazines possess antifungal and anticancer activity. The compounds have the structure: ##STR2## wherein x has a value of 1, 2 or 3; R.sub.1 is a lower alkyl group, e.g., an alkyl group containing up to six carbon atoms such as methyl, ethyl, propyl, butyl, etc.; R.sub.2 is a member selected from the group consisting of hydrogen, alkyl radicals having from about one to about 12 carbon atoms, preferably from about one to about 6 carbon atoms; alkenyl radicals having from about two to about 15 carbon atoms, preferably from about two to about 10 carbon atoms; cycloalkyl radicals having from about three to about 20 carbon atoms, preferably from about three to about 15 carbon atoms; aralkyl and alkaryl radicals having from about six to about 20 carbon atoms, preferably from about six to about 15 carbon atoms; a halogen radical, e.g., chlorine, fluorine, bromine and iodine, provided that when x has a value o 1 and R.sub.2 is in the para position and R.sub.3 and R.sub.4 are both hydrogen, R.sub.2 is not chlorine; a hydroxyl group; an amino group; an alkoxy or aryloxy group; a carboxyl group or an alkylcarboxyl group having from about one to about 10 carbon atoms, preferably from about one to about 5 carbon atoms; an alkylthio group or an arylthio group having from about one to about 20 carbon atoms, preferably from about one to about 15 carbon atoms; a sulfonic acid group or alkyl- or arylsulfonyl group having from about one to about 20 carbon atoms, preferably from about one to about 15 carbon atoms; an alkyl- or arylsulfinyl group having from about one to about 20 carbon atoms, preferably from about one to about 15 carbon atoms; an alkyl- or aryl mono- or diamino group having from about one to about 20 carbon atoms, preferably from about one to about 15 carbon atoms; a hydrocarbyl group, such as defined above, carrying halogen, hydroxyl, amino, alkoxy or aryloxy, and when taken together with the aromatic ring to which it is attached, a fused ring structure such as naphthyl; and R.sub.3 and R.sub.4 are either both hydrogen or one is hydrogen and the other is a lower alkyl group. The disclosure of this patent is incorporated herein by reference.